Chronic wound treatment has become a major problem for health care systems worldwide, representing a great economic and public health challenge. The current increase of risk factors such as, ageing population, smoking, diabetes and obesity can complicate and slow down the wound healing process, causing difficult-to-heal wounds.
Several palliative treatments including hyperbaric oxygen, negative pressure and surgical debridement are currently being used for the treatment of chronic wounds in elderly people. In addition, a wide range of commercial synthetic dressings for the treatment of chronic ulcers are available in the market, although showing a limited healing efficacy.
The epidermal growth factor (EGF) plays an important role in tissue regeneration and repair by stimulating cell migration, differentiation and proliferation, and also by promoting granulation tissue formation. From a clinical point of view, EGF has been used to enhance wound healing, especially in diabetic foot ulcers. Evidences of the beneficial effects of topical EGF application in low-grade, neuropathic ulcers have been shown in clinical trials; however, the effect of topical EGF formulation can be abated, especially in high-grade wounds, since an increased protease activity has been identified in this type of wounds. Rengen-D 150™ is a gel containing 150 μg/g of recombinant human epidermal growth factor (rhEGF) manufactured in India for the treatment of grade I or II diabetic ulcers. It requires twice daily administration, for an average treatment time of 6 weeks. Heberprot®, a lyophilised formulation containing 75 μg of rhEGF, is administered three times weekly by intralesional injections. It is marketed in Algeria, Argentina, Colombia, Cuba, the Dominican Republic and Venezuela. A pilot study carried out in 20 diabetic patients demonstrated Herberprot® as a feasible and safe treatment to promote healing of chronic wounds in patients with full thickness ulcers. However, rhEGF short half-life requires continuous exposure (at least 6-12 hours) to enhance the mitogenic effect on epithelial cells. Therefore, in order to achieve a significant therapeutic effect in wound healing, it is necessary to optimise the administration of growth factors such as rhEGF, in terms of dose, delivery system and safety. For that purpose, Chu et al., 2010 (Nanotechnology promotes the full-thickness diabetic wound healing effect of recombinant human epidermal growth factor in diabetic rats”, Wound Repair Regen 2010; 15:499-505) have developed a method to prepare nanoparticles of the polymer poly(lactic-co-glycolic acid) (PLGA) with a 2% rhEGF content. rhEGF encapsulation efficiency was 85.6% and presented a controlled release of biologically active rhEGF for up to 24 hours. Topical application once daily of these nanoparticles on full-thickness wounds induced in diabetic rats promoted higher fibroblast proliferation levels and fastest healing rates, compared with non-encapsulated rhEGF.
In addition, patent EP 1 987 817 B1 claims the process of producing polymeric microspheres containing rhEGF for intralesional infiltration into the lower limbs of diabetic patients to prevent diabetic limb amputation. Developed microspheres with a 1.6-2.4% rhEGF content showed a rhEGF controlled release of 5 and 10 μg per day during 14 days and a faster injury healing in humans compared with equivalent amounts of non-encapsulated rhEGF.
Surprisingly, the inventors have developed lipid nanoparticles comprising epidermal growth factor with high encapsulation efficiencies, that applied in a topical formulation twice a week, improve wound healing.